Osteoporosis

General Features

Osteoporosis is accelerated bone loss. Normally, there is loss of bone mass with aging, perhaps 0.7% per year in adults. However, bone loss is greater in women past menopause than in men of the same age. The process of bone remodeling from resorption to matrix synthesis to mineralization normally takes about 8 months--a slow but constant process. Bone in older persons just isn't as efficient as bone in younger persons at maintaining itself--there is decreased activity of osteoblasts and decreased production of growth factors and bone matrix. (Sambrook and Cooper, 2006)

This diagram illustrates changes in bone density with aging in women. The normal curve (A) steepens following menopause, but even by old age the risk for fracture is still low. A woman who begins with diminished bone density (B) even before menopause is at great risk, particularly with a more accelerated rate of bone loss. Interventions such as postmenopausal estrogen (with progesterone) therapy, the use of drugs such as the non-hormonal compound alendronate that diminishes osteoclast activity, and the use of diet and exercise regimens can help to slow bone loss (C) but will not stop bone loss completely or restore prior bone density. Diet and exercise have a great benefit in younger women to help build up bone density and provide a greater reserve against bone loss with aging. (Winslow et al, 2009)

The World Health Organization (WHO) has defined osteoporosis as a spinal or hip bone mineral density (BMD) that is 2.5 standard deviations or more below the mean BMD for healthy, young women, measured by dual energy x-ray absorptiometry (DEXA). The WHO defines osteopenia as a spinal or hip BMD between 1 and 2.5 standard deviations below the mean for healthy, young women. (Sweet et al, 2009)

Fracture risk can be estimated at: http://osteoed.org/tools.php

Bone Metabolism

Bone metabolism is controlled by a variety of factors.

Parathyroid hormone receptors are found on osteoblasts. Parathyroid hormone (PTH) stimulation of osteoblasts increases osteoblast production of receptor activator of nuclear factor kappa-B ligand (RANKL). Hematopoietic cell precursors stimulated by M-CSF give rise to osteoclasts that express RANK receptor. The RANKL/RANK interaction stimulates differentation of the osteoclasts so that they can resorb bone. Osteoblasts also produce a decoy receptor called osteoprotegerin (OPG) that binds to RANKL and prevents the RANKL/RANK interaction.

Prolonged corticosteroid therapy leads to a reduction in osteoblasts and osteoclasts. However, there is prolonged survival of osteoclasts, leading to an imbalance with net bone loss. In addition, osteocyte apoptosis is enhanced to reduce bone strength even before there is marked loss of bone mineral density. (Weinstein, 2011)

Risk Factors

Risk factors for osteoporosis include:

Female sex

Age > 70 years

Caucasian or Asian race

Early onset of menopause

Longer postmenopausal interval

Inactivity, especially lack of weight bearing exercise

Osteoporosis can be classified as primary or secondary. Primary osteoporosis is simply the form seen in older persons and women past menopause in which bone loss is accelerated over that predicted for age and sex. Secondary osteoporosis results from a variety of identifiable conditions that may include: (Sweet et al, 2009)

Metabolic bone disease, such as hyperparathyroidism

Neoplasia, as with multiple myeloma or metastatic carcinoma

Malnutrition

Drug therapy, as with corticosteroids

Prolonged immobilization

Weightlessness with space travel

Modifiable risk factors that may potentiate osteoporosis include:

Smoking

Alcohol abuse

Excessive caffeine consumption

Excessive dietary protein consumption

Lack of dietary calcium

Lack of sunlight exposure (to generate endogenous vitamin D)

Diagnosis

Diagnosis of osteoporosis is made by three methods:

Radiographic measurement of bone density

Laboratory biochemical markers

Bone with pathologic assessment

Of these three the best is radiographic bone density measurement. A variety of techniques are available, including single-photon absorptiometry, dual-photon absorptiometry, quantitative computed tomography (QCT), dual x-ray absorptiometry (DEXA), and ultrasonography. Most often, site specific measurements are performed. The most common sites analyzed are those with greatest risk for fracture: hip, wrist, and vertebrae. The forearm and heel are more easily measured using single-photon absorptiometry, quantitative computed tomography, and quantitative ultrasonography, but these sites are typically unresponsive to therapy and give less information about response to therapy. Hip (femur) and vertebra can be easily measured by DEXA with an instrument dedicated to this task.

A graphical display of a DEXA scan for the hip (femur) is shown below, comparing bone mineral density (BMD) to age and T-score (in standard deviations above or below the comparable healthy young adult woman's mean BMD). The asterisk representing a woman at age 48 is within the expected range for age. The circle marks the BMD for a woman age 60 and is concerning for greater bone loss from osteopenia (-1 to -2.5) but not yet osteoporosis. The X marks the BMD for a woman age 76 and is in the range of osteoporosis (> -2.5) with increased risk for fracture.

Increased risk for fracture correlates with decreasing bone density. Serial measurements over time can also give an indication of the rate of bone loss and prognosis (Bonnick and Shulman, 2006) (El Maghraoui and Roux, 2008).

Biochemical markers for bone turnover include bone alkaline phosphatase, osteocalcin in serum and deoxypyridinoline and pyridinoline in urine. (Bonnick and Shulman, 2006)

Alkaline phosphatase, which reflects osteoclast activity in bone, lacks sensitivity and specificity for osteoporosis, because it can be elevated or decreased with many diseases. It is increased with aging. Fractionating alkaline phosphatase for the fraction more specific to bone doesn't increase usefulness that much.

Osteocalcin, also known as bone gamma-carboxyglutamate. It is synthesized by osteoblasts and incorporated into the extracellular matrix of bone, but a small amount is released into the circulation, where it can be measured in serum. The levels of circulating osteocalcin correlate with bone mineralization, but are influenced by age, sex, and seasonal variation. Laboratory methods also vary.

The bone resorption markers in urine are breakdown products of type I collagen and include pyridinium crosslinks known as pyridinoline and deoxypyridinoline. They reflect bone remodeling but not the status of bone mineral density.

Bone biopsy is not often utilized for assessment of bone density. This test has limited availability, and is most often performed as a research technique for analysis of treatment regimens for bone diseases. Bone biopsy involves double tetracycline labelling to determine appositional bone growth. Doses of tetracycline are given weeks apart, and the bone biopsy is embedded in a plastic compound, sliced thinly, and examined under fluorescent light, where the lines of tetracycline (which autofluoresce) will appear and appositional growth assessed. Osteomalacia, for example, has diminished appositional growth. (Malluche et al, 2007)

Consequences of Osteoporosis

Osteoporotic bone is histologically normal in its composition--there is just less bone. This results in weakened bones that are more prone to fractures with trauma, even minor trauma. The areas most affected are:

Hip (femoral head and neck)

Wrist

Vertebrae

Hip fractures that occur, even with minor falls, can be disabling and confine an elderly person to a wheelchair. It is also possible to surgically put in a prosthetic hip joint. Wrist fractures are common with falls forward with arms extended to break the fall, but the wrist bones break too. Vertebral fractures are of the compressed variety and may be more subtle. Vertebral fractures may result in back pain. Another consequence is shortening or kyphosis (bending over) of the spine. This can lead to the appearance of a "hunched over" appearance that, if severe enough, can even compromise respiratory function because the thorax is reduced in size.

Persons suffering fractures are at greater risk for death, not directly from the fracture, but from the complications that come from hospitalization with immobilization, such as pulmonary thromboembolism and pneumonia.

Osteoporosis is so common that, on average, about 1 in 2 elderly Caucasian women will have had a fracture. In contrast, only about 1 in 40 men of similar age will have had a fracture. Men start out with a greater bone mass to begin with, so they have a greater reserve against loss. However, that is still a large number of men with osteoporosis. (Binkley, 2009)

Prevention Strategies

The best long-term approach to osteoporosis is prevention. If children and young adults, particularly women, have a good diet and get plenty of exercise, then they will build up and maintain bone mass. This will provide a good reserve against bone loss later in life. Exercise places stress on bones that builds up bone mass, particularly skeletal loading from muscle contraction with weight training exercises. However, any exercise of any type is better than none at all, and exercise also provides benefits for prevention of cardiovascular diseases that are more common in the elderly. Athletes tend to have greater bone mass than non-athletes. Exercise in later life will help to retard the rate of bone loss. (Sweet et al, 2009)

A healthy diet should include not only enough calcium and vitamin D, but also other nutrients, including a range of vitamins and minerals found in a diet that contains fruit and vegetables, as well as dairr products. Appropriate protein intake has an anabolic effect to build osteoid matrix. (Tucker, 2009)

Treatment

Persons with osteoporosis may benefit from an improved diet, including supplementation with vitamin D and calcium, and moderate exercise to help slow further bone loss.

Most drug therapies work by decreasing bone resorbtion. At any given time, there is bone that has been resorbed but not replaced, and this accounts for about 5 to 10% of bone mass. By decreasing resorbtion of bone, a gain in bone density of 5 to 10% is possible, taking about 2 to 3 years. However, no drug therapy will restore bone mass to normal. Women past menopause with accelerated bone loss may benefit from hormonal therapy using estrogen with progesterone. The estrogen retards bone resorption and thus diminishes bone loss. This effect is most prominent in the first years after menopause, while risks from hormone replacement therapy increase. (Nelson et al, 2002)

One of the more common non-estrogen therapies is the use of bisphosphonates such as alendronate or risedronate that act an an inhibitor of osteoclastic activity. Bisphosphonates may be beneficial, particularly in women who cannot tolerate estrogen therapy. Bisphosphonaes are effective in inhibiting bone loss after menopause. In one study risedronate has shown effectiveness in reducing the risk of hip fracture among elderly women with osteoporosis. Short term adverse effects of bisphosphonate therapy include esophagitis, musculoskeletal pain, ocular inflammation, and hypocalcemia. Long term adverse effects include increased risk for esophageal cancer, osteonecrosis of the jaw, femoral fracture, and atrial fibrillation. (Kennel and Drake, 2009)

Raloxifene is a selective estrogen receptor modulator (SERM) that may also replace estrogen therapy. Raloxifene can act in concert with estrogen in bone to inhibit resorbtion and decrease the risk for fractures. Though raloxifene inhibits bone resorbtion, it does not have an anabolic effect. Additional potential benefits from raloxifene therapy include decreased risk for breast cancer, because raloxifene acts antagonistically to estrogen on the uterus. Conversely, raloxifene acts in concert with estrogen to protect against and reduce atherogenesis. (Jordan, 2007)

Teriparatide is a recombinant human parathyroid hormone administered by subcutaneous injection which binds to specific high-affinity cell-surface receptors in bone and kidney, similar to the 34 N-terminal amino acids of parathyroid hormone, and has the same physiological actions on bone and kidney. Daily administration of teriparatide stimulates new bone formation by promoting osteoblastic activity over osteoclastic activity, improving trabecular bone architectural remodelling and increasomg bone mass. (Cappuzzo and Delafuente, 2004) (Sweet et al, 2009)

Denosumab is a human monoclonal antibody that binds to and inhibits the receptor activator of nuclear factor-kappaB ligand (RANKL) that is elaborated by osteoblasts. The RANKL interacting with RANK receptor expressed on osteoclasts is affected by this drug, leading to reduced osteoclast activation and survival, thus inhibiting bone resorbtion that helps increase bone mineral density. Thus, densosumab mimics osteoprotegrin that is reduced in osteoporosis. (Moen and Keam, 2011 )

Other drug therapies are less commonly employed. Calcitonin, a hormone that decreases bone resorbtion, may be taken by injection or by nasal spray. Sodium fluoride can increase the measured bone density in vertebra, but seems to have no overall effectiveness in reducing vertebral fracture. Zoledronic acid has shown effectiveness in treating bone loss. (Rahmani and Morin, 2009)